Nomogram for predicting outcomes in elderly women with mucinous breast cancer: A retrospective study combined with external validation in southwest China

Abstract Objective Mucinous breast cancer (MBC) is a kind of breast cancer (BC), which is rare in clinic, mainly for women, because of the low incidence rate, so there is no unified standard treatment protocol. Elderly patients have a poor prognosis due to their combined comorbidities. This study aims to investigate the effect of surgery and chemoradiotherapy on the prognosis of elderly female MBC patients and construct nomograms for predicting the OS and CSS in elderly female MBC patients. Methods Data for female MBC patients over 65 years are obtained from the Surveillance, Epidemiology and End Results (SEER) database, patients were divided into two groups: the training set and the validation set. External validation data of the prediction model were provided by Kunming Hospital of Traditional Chinese Medicine. We used Cox regression modeling, which was used to identify independent risk factors affecting patient prognosis. After avoiding confounding bias according to the multifactorial Cox regression model, we used these screened statistically significant results to construct column‐line plots. The performance of the model was tested using the consistency index (c‐index), the calibration curve, and the area under the operating characteristic curve of the receiver (AUC). Subsequently, we used decision curve analysis (DCA) to examine the potential clinical value of our nomograms. Results A total of 8103 elderly MBC female patients were extracted from the database SEER and were assigned to the training and validation set, randomly. A total of 83 patients from Kunming Hospital of Traditional Chinese Medicine were used in the external verification set. After multifactorial Cox regression analysis, we found that age, race, T‐stage, M‐stage, surgical approach, radiotherapy, and tumor size were independent risk factors for OS in elderly MBC patients. Similarly, independent risk factors of CSS included age, marital status, N stage, M stage, surgical approach, chemotherapy, and tumor size. The C‐index for the OS training, validation, and external verification set were 0.731 (95%CI 0.715–0.747), 0.738 (95%CI 0.724–0.752), and 0.809 (95%CI 0.731–0.8874). The C‐index of the training set, the validation set, and external verification set for CSS were 0.786 (95%CI 0.747–0.825), 0.776 (95%CI 0.737–0.815), and 0.84 (95%CI0.754–0.926), respectively. The AUC, calibration curves and DCA also showed good accuracy. Conclusions In this study, we construct a new nomogram to predict the prognosis of elderly patients with MBC. The nomograms have undergone internal and external validation and have been confirmed to have good clinical applicability. At the same time, we found that for elderly female MBC patients, surgery and radiotherapy significantly benefit their survival, but chemotherapy is not conducive to patient survival.

lance, Epidemiology and End Results (SEER) database, patients were divided into two groups: the training set and the validation set.External validation data of the prediction model were provided by Kunming Hospital of Traditional Chinese Medicine.We used Cox regression modeling, which was used to identify independent risk factors affecting patient prognosis.After avoiding confounding bias according to the multifactorial Cox regression model, we used these screened statistically significant results to construct column-line plots.The performance of the model was tested using the consistency index (c-index), the calibration curve, and the area under the operating characteristic curve of the receiver (AUC).Subsequently, we used decision curve analysis (DCA) to examine the potential clinical value of our nomograms.
Results: A total of 8103 elderly MBC female patients were extracted from the database SEER and were assigned to the training and validation set, randomly.A total of 83 patients from Kunming Hospital of Traditional Chinese Medicine were used in the external verification set.After multifactorial Cox regression analysis, we found that age, race, T-stage, M-stage, surgical approach, radiotherapy, and tumor size were independent risk factors for OS in elderly MBC patients.Similarly, independent risk factors of CSS included age, marital status, N stage, M stage, surgical approach, chemotherapy, and tumor size.The C-index for the OS training, validation, and external verification set were 0.731 (95%CI 0.715-0.747),0.738 (95%CI 0.724-0.752),and 0.809 (95%CI 0.731-0.8874).The C-index of the training set, the validation set, and external verification set for CSS were 0.786 (95%CI 0.747-0.825),0.776 (95%CI 0.737-0.815),and 0.84 (95%CI0.754-0.926),respectively.The AUC, calibration curves and DCA also showed good accuracy.
Conclusions: In this study, we construct a new nomogram to predict the prognosis of elderly patients with MBC.The nomograms have undergone internal and external validation and have been confirmed to have good clinical applicability.At the same time, we found that for elderly female MBC patients, surgery and radiotherapy significantly benefit their survival, but chemotherapy is not conducive to patient survival.

| INTRODUCTION
Breast cancer (BC) is one of the most common type of cancers worldwide and can lead to a large number of cancer-related deaths. 1 In the United States, about 284 200 new cases of BC in 2021, among them, 281 550 are women, and total of 44 130 deaths, with 43 600 women. 2 This shows that female patients dominate breast cancer.
Mucinous breast cancer (MBC) is a clinically rare pathologic type of BC that accounts for approximately 1% 6% of primary BC and is more common in older postmenopausal women. 3It has a better prognosis compared with other breast malignancies (such as ductal or lobular variants). 4The overall prognosis of MBC is favorable.The 5-year overall survival rate (OS) of MBC is reported to be 95% to 98.9%, and the 10-year overall survival rate exceeds 90%. 5,6However due to the low incidence and clinical rarity, there is no uniform standard treatment regimen for MBC patients.
Results derived from single-center clinical studies are prone to bias due to the low incidence of MBC.The Surveillance, Epidemiology, and End Results (SEER) is a National Cancer Institute database that records the incidence, mortality, and morbidity of millions of cancer patients in selected states and counties in the United States (US), which has the advantage of being updated in real time and having a large number of cases, covering more than 30% of the US population.SEER database-based studies often represent population-based extensive data studies, and the results are often more reliable than single-center studies.The prognosis of MBC is often influenced by multiple factors.However, previous oncological prognosis was usually assessed by performing a conventional TNM staging system.Because the TNM staging system contains too few variables to predict some prognostic factors for patients in actual situations, it is difficult to propose personalized treatment options for each patient.The nomogram is a computer-based predictive model that is presented graphically and is exceptionally friendly to users and can help clinicians to make personalized predictions. 70]   12 However, there are no current studies to construct both the nomograms of OS and CSS in MBC patients and explore the differences between the factors influencing them.
The MBC patients were mostly female, and the vast majority of MBC occurred in postmenopausal women.A single-center study conducted by Emilia Marrazzo et al. showed that the median age of MBC patients was 64.4 years. 13In addition, the WHO and Medicare define older adults as over 65 years old. 14,15However, no corresponding nomogram has been developed for elderly female MBC patients.Moreover, their non-cancer-specific death may lead to a low overall OS due to comorbidities, making OS and CSS different.Therefore, it is more important to construct a nomogram predicting OS and CSS in elderly MBC patients.Therefore, this study aims to construct nomograms to predict OS and CSS of elderly female MBC patients and further analyze the effects of surgical methods and chemoradiotherapy on OS and CSS through the KM curve in order to provide more reasonable guidance for the treatment of elderly female MBC patients.

| Dataset Description and Preprocessing
Data from patients diagnosed with BC during the period 2000-2018 were extracted from the SEER database.The target population of this study was female patients diagnosed with MBC aged over 65.
This study followed the research guidelines published by the SEER database.
The breast cancer-related clinical information contained in the SEER database is the same as the previous study. 16The inclusion criteria include the following: (1) Age over 65 (including 65 years old);

| Statistical analysis
Continuous variables used in this study conformed to normal distribution by testing and were therefore described using means and standard deviations.Differences between groups were analyzed using χ2 test or non-parametric U test.Categorical variables were described using frequencies for (%), and we used the χ2 test to detect differences between groups.Also, performing Cox risk regression model analysis screen independent risk factors that affect the prognosis of elderly patients with MBC.Differences in patient survival were analyzed through the K-M curves and log-rank test.R version 4.2.0 and SPSS 25.0 was used for statistical analysis.The R package used were based on "Survival," "gg DCA," "Dyn Nom," and "RMS".P-values less than .05were considered statistically significant.

F I G U R E 1 Flowchart for inclusion and exclusion of elderly female patients with MBC.
T A B L E 1 Clinicopathological characteristics of elderly female patients with MBC.

| Nomograms construction and validation
The results of univariate and multivariate OS and CSS are presented in Tables 2 and 3. We developed new nomograms by combining the results of independent risk factors that can predict the outcomes in elderly female MBC patients (Figure 2).Radiotherapy, surgical mode,

| Clinical application of nomograms
Decision curve analysis result presented that the nomogram had fine clinical potential value for the prognosis of elderly female MBC patients (Figure 5), and all were significantly better than the conventional TNM staging.The risk value of each patient was calculated according to the nomogram, and the best cut-off value was calculated.The patients were divided into high-risk and low-risk groups.The K-M curve showed that the prognosis of the high-risk group was significantly worse than that of the low-risk group (Figure 6).The OS of patients without surgery was the lowest, followed by radical mastectomy, and the OS of patients with local tumor resection was the highest.OS was higher in patients treated with radiotherapy, and better survival benefit in high-risk patients than low-risk patients (Figure 7).
For CSS, the trend of surgical methods was similar to that of OS.Patients with higher CSS were treated by surgery, and those with the highest CSS were treated by local tumor resection.Chemotherapy is a risk factor for prognosis.For the high-risk group, patients receiving chemotherapy have lower CSS.In contrast, chemotherapy had little effect on CSS in the low-risk patients (Figure 8).

| DISCUSSION
Although the survival rate of MBC patients is relatively ideal, the survival rate of patients in elderly remains low due to the effects of comorbid- Age is strongly associated with the onset of many cancers, for example prostate cancer, bladder cancer, and other tumors. 17,18The incidence of BC is also age-related, and MCB is a disease that occurs in elderly women, with a mean age of patients significantly more significant than the other histological subtypes. 19Meanwhile, a clinical trial evaluating the influence of age on mortality 10 years after diagnosis found that older of age at diagnosis, the increased mortality in BC. 20 Our study found that for female MBC patients over 65 years old, age affected both the OS and CSS and the older the age, the worse the patient prognosis, in line with the conclusions of previous studies. 21The reasons may be as follows: First, most elderly patients have combined comorbidities.Moreover, due to their poor functional status, most elderly patients do not choose an active treatment, resulting in a relatively poor prognosis. 22rital status is also a risk factor associated with many cancer outcomes.Most studies have found that married status favors prognosis for cancer patients; for example, in colon cancer, divorced/separated/widowed patients are associated with higher mortality when compared with married patients. 23Studies have shown that unmarried or widowed women have a e a higher diagnostic risk and worse survival outcomes than married women.Therefore, more attention should be given to single female BC patients. 24The clinical nomogram constructed by Fu et al. to predict the survival outcome of early MBC showed a better CSS with married patients. 12Our study divided the marital status of MBC patients into four types, including single, divorced, widowed as well as married.For elderly patients with MBC, married patients have a better CSS, with little difference in survival among single, divorced, and widowed patients.Considering that married patients can get more financial support and care and more emotional comfort.
Race is strongly associated with the incidence and mortality of BC patients.In recent years, the mortality of white patients has decreased due to early detection and improved treatment options.
But overall, cancer incidence in African Americans and Hispanic Americans continues to rise. 25The predictive model constructed by Pan et al. showed that race was an independent risk factor affecting the OS of patients with inflammatory BC. 8 Min et al. found that race can affect regional lymph node metastasis risk in patients with T1-2 MBC. 26 The predictive model for MBC constructed by Zhu et al.
showed that race was an independent risk factor for OS in MBC patients. 11Our results also showed that ethnicity was strongly related to OS in older female MBC patients but it had no effect on the CSS in MBC patients.
TNM stage is the traditional way to evaluate tumor prognosis.
The prognosis of most cancer patients is closely related to the TNM stage.Our study found that the TNM stage also seriously affected OS and CSS in older female MBC patients.Overall, the higher the TNM stage, the worse the prognosis, and previous studies showed consistent. 11,12In addition, tumor size is also a key factor which affect the survival of cancer patients.However, the AJCC staging system suggested that tumor size may not be an important prognostic factor for MBC, because the vast majority of the tumor volume is mucin. 27r some time in the past, patients with tumor size >2 cm who should receive adjuvant chemotherapy was written into the NCCN guidelines.However, at this stage, the guidelines have been revised; regardless of this breast cancer patient's T-stage at any stage, patients with lymph node metastases are considered to have an indication for chemotherapy as long as they have. 28Therefore, tumor size is crucial for the choice of treatment regimen for patients with MBC.However, some scholars have pointed out that tumor size may not be accurately measured, which may lead to bias in the judgment of prognosis. 29wever, the nomogram constructed by Wu et al. shows that tumor size is an independent risk factor for predicting the probability of lymph node metastasis in MBC patients, and the larger the tumor, the higher the risk of lymph node metastasis. 30For elderly MBC patients, our results also show that tumor size for patients with OS and CSS has a significant impact; the larger the tumor, the lower the OS and CSS, considering the bigger the tumor, the more difficult the operation and for elderly patients, due to a variety of comorbidities, the larger the tumor, the worse the tolerance of patients.
At present, for the treatment of BC.Surgical methods for BC include local tumor resection, partial mastectomy, and radical mastectomy.However, for MBC, there is no unified and standardized treatment plan due to its low incidence, and its treatment method refers to invasive BC.The current mainstream treatment strategy is surgery combined with adjuvant therapy, but its survival benefit is not clear.
Recently, local treatment for stage T1-2 MBC has recommended breast preservation, which has a better prognosis than radical mastectomy. 31The study by Kaisu Ojala et al. showed that OS and elderly breast cancer patients undergoing surgery had better CSS, suggesting that surgical treatment also seems to be safe in the elderly patient population. 32The study by Hu et al. showed that surgery is a protective factor for the overall survival of MBC patients. 21is study found that most of the MBC patients received surgical  Radiation therapy is one of the most important therapeutic measures for many cancer patients.A randomized controlled trial found that the ipsilateral breast tumor recurrence rate without radiotherapy was relatively high for in patients ≥65 with early BC compared to women receiving radiotherapy. 33But it is increasingly recognized that RT has little benefit in women aged ≥65 who are estrogen receptor positive and with a tumor size ≤3 cm. 34 neoadjuvant chemotherapy has become the preferred therapeutic strategy. 36However, the literature has reported that the low chemotherapy efficacy of MBC patients is mainly due to the high proportion of mucus to the total MBC cell volume, forming a large mucin pool, leading to inconsistent clinical or imaging evaluation of chemotherapy efficacy and with mucinous carcinoma pathology. 37Despite studies showing that chemotherapy is effective in eliminating malignant cells.
However, the mucin pool still exists. 38This study found that a very small number of elderly female MBC patients received chemotherapy, and chemotherapy does have no survival benefit in elderly patients with MBC, especially for patients with high risk; chemotherapy is more harmful to CSS, considering the side effects of chemotherapy and the low-risk patients.However, for low-risk patients, chemotherapy has little impact on their CSS.
This study explored the influencing factors associated with OS and CSS in elderly female patients with MBC using the SEER database, and we successfully developed nomograms of OS and CSS.
However, this study still has some limitations.For example, the HER2 indicators in breast cancer patients are extremely important for patient prognosis, but the SEER database did not begin to include these indicators until 2010, so many breast cancer patients lack relevant data, which will bias the results.Second, this study was retrospective, which would confer selection bias.However, it have included many important key variables and was internally validated, so it will not be greatly biased.Moreover, the KM curve analysis found that the 3-year, 5-year, and 8-year OS was significantly lower than the CSS in both the high-risk and low-risk groups.This thus reflects a higher proportion of non-cancer-specific deaths in older female MBC patients.Follow-up studies continuing to explore the risk factors associated with noncancer-specific death in older MBC patients may be of great clinical value.

| CONCLUSIONS
This study explored the independent risk factors for OS and CSS in elderly female MBC patients, we found that race, age, T stage, M stage, radiotherapy, surgery, and tumor size were independent risk factors for OS in elderly MBC patients.Age, marital status, NM stage, surgery, tumor size, and chemotherapy were independent risk factors for CSS.Independent risk factors were screened according to COX multifactorial, and based on these factors, nomograms were constructed to predict OS and CSS in elderly MBC patients.Through a series of validations, our study confirmed that these new nomograms have better accuracy compared with previous studies.It can provide effective help to clinicians when they conduct the diagnosis and treatment of elderly MBC patients.Our study also found that surgery and radiotherapy favored survival in elderly female MBC patients, while chemotherapy had little survival benefit.Moreover, this study found that the OS of elderly female MBC patients was significantly lower than the CSS, suggesting a higher proportion of non-cancer-specific deaths, so the follow-up studies will continue to explore the non-cancer-specific deathrelated risk factors.

3 |
NOMOGRAM CONSTRUCTION AND VALIDATIONElderly female MBC patients data was extracted from the SEER database, and cases collected from Kunming Hospital of Traditional Chinese Medicine were used to perform external validation of the model.First, we identified the relevant factors what affecting patients' prognosis.These risk factors were obtained from the training set.Then, using the multivariate Cox proportional regression model screen the independent risk factors related to the prognosis of MBC patients after excluding the bias caused by the single factor.Based on the results of the multivariate regression analysis, we constructed new nomograms for predicting outcomes in elderly female MBC patients.Subsequently, we used calibration curves to test the prediction power of the constructed nomograms at 3, 5 and 8 years.Meanwhile, the consistency index (c-index) and the area under the curve (AUC), and decision curve analysis (DCA) were performed to fully test the clinical application value of the novel nomograms.To facilitate the use of the researchers, we also made a web version of the nomograms, with links placed in the availability of data and material section.

M
stage, age, and race were the most important factors affecting patients' OS.Second, tumor size and T stage were also essential factors of OS.Tumor size, surgical mode, M stage, and age were the most important factors for CSS, and second, chemotherapy, N stage, and marital status had less effect on patients' CSS.We validated the accuracy and discrimination of the nomograms.The C-index for the OS were 0.731 for training set, 0.738 for validation set and 0.809 for the external verification set.The C-index for CSS were 0.786 in the training set, 0.776 in the validation set, and 0.84 in the external verification set.The C-index indicates fine recognition of the prediction model of the nomograms.The calibration curve also illustrates the fine prediction accuracy of the nomograms (Figure3), the FigureS1showed the calibration curve for OS and CSS in the external verification set, all the results indicated that the nomogram has good accuracy.In the OS training set, the AUC was 74.7, 75.2, 75.4; in the OS validation set, the AUC were 76.0, 75.7, 75.8.In the CSS training set, the AUC was 81.1, 79.0, 75.7; in the CSS validation set, the AUC was 79.5, 79.9, 76.1, respectively (Figure4).In the external verification set, the AUC was 88.1, 88.6, and 67.7 for OS at 3, 5, and 8 years; the AUC was 82.0, 82.5, and 77.3, respectively for CSS at 3, 5, and 8 years (FigureS2).The above results show that the nomograms we constructed to predict OS and CSS are very discriminative.

F I G U R E 2
Nomograms predicting 3-, 5-, and 8-year prognosis in elderly female patients with MBC.(A) Nomogram predicting OS in elderly female patients with MBC.(B) Nomogram predicting CSS in elderly female patients with MBC.
ities.Second, there is no unified treatment standard due to MBC low morbidity, which may affect patient prognosis.However, many factors affect patient prognosis, including various clinical case factors.Therefore, F I G U R E 3 Calibration curves of nomograms predicting 3-, 5-, and 8-year prognosis of elderly female MBC patients.(A) Calibration curves of nomograms on OS in the training set.(B) Calibration curves of nomograms predicting OS in the validation set.(C) Calibration curves of nomograms predicting CSS in the training set.(D) Calibration curves of nomograms predicting CSS in the validation set.this study, based on the SEER database with big data, explored univariate and multi factors affecting OS and CSS in MBC patients.We found that age, race, T and M stage, operation method, tumor size and radiotherapy were independent risk factors of OS in patients with MBC.In contrast, age, marital, N and M stage, surgical mode, tumor size and chemotherapy were play an important role in CSS.

F I G U R E 4
AUC predicts prognosis in elderly female patients with 3-, 5-, 8 year MBC.(A) AUC of OS in the training set.(B) AUC of OS in the validation set.(C) AUC of CSS in the training set.(D) AUC of CSS in the validation set.

5
DCA of the nomograms for predicting OS and CSS.(A) DCA of the nomograms for predicting OS in the training set.(B) DCA of the nomograms for predicting OS in the validation set.(C) DCA of the nomograms for predicting CSS in the training set.(D) DCA of the nomograms for predicting CSS in the validation set.

F
I G U R E 6 K-M curves in low-risk patients and high-risk group.The OS rates of patients in the high-risk group are significantly lower than those in the low-risk group in both the training set (A) and the validation set (B).The same results were observed in the training set (C) and validation set (D) for CSS rate.
treatment, and the OS and CSS of MBC patients benefited from surgical treatment, the results of the KM curve analysis showed that patients undergoing local resection of the tumor had the best prognosis, followed by patients treated with local mastectomy, while patients undergoing radical mastectomy had a worse prognosis than the first two surgical procedures.Considering that elderly MBC patients are prone to complicated comorbidities, radical surgery is poorly tolerated.

F I G U R E 7
Kaplan-Meier curves of OS rate of patients with different surgery mode and radiotherapy.(A) The OS rate of patients underwent different surgery.(B) The OS rate of patients in patients with or without radiotherapy.(C) The OS rate of patients in the high-risk group with or without radiotherapy.(D) The OS rate of patients in the low-risk group with or without radiotherapy.
While the randomized clinical trial conducted by Jayant S Vaidya et al. showed that It indicates that the immediate single-dose of target-iort for risk adaptation during tumor resection is effective alternative to EBRT in early-stage BCpatients.35Our study found that radiotherapy favored the OS of elderly female MBC patients, and after dividing the patients into different groups, high-risk patients benefited more from RT, while it had little effect on OS in low-risk patients.Considering that low-risk patients can achieve better survival through surgical treatment, radiotherapy has little benefit for low-risk patients.Moreover, only a few of high-risk patients receiving RT may bias the results.Chemotherapy is also one of the adjuvant treatment measures for most cancers.In clinical practice, with an increasing number of patients with triple-negative BC with TNBC and her2-positive BC, F I G U R E 8 Kaplan-Meier curves of CSS rates in patients with different surgical approaches and chemotherapy.(A) CSS rates in patients with different surgical approaches.(B) CSS rates in patients with and without chemotherapy.(C) OS rates in patients in the high-risk group with or without chemotherapy.(D) OS rates in patients in the low-risk group with or without chemotherapy.
Zhu et al. developed a nomogram that could predict OS in MBC patients, suggesting that age, ethnicity, T stage, M stage, surgery, and radiotherapy were independent risk factors for OS in MBC patients. 11The nomogram developed by Fu et al.Can predicts the CSS of MBC patients with early stage.
Univariate and multivariate analyses of OS in training set.
T A B L E 1 (Continued) T A B L E 3 Univariate and multivariate analyses of CSS in training set.4.1 | Baseline characteristics of the patients A total of 8103 female patients diagnosed with MBC and aged over 65 years old (including 65) from SEER database were assigned to two cohorts: the training set (N = 3928) and the validation set (N = 4175).A total of 83 patients from Kunming Hospital of Tradi-